Abstract
Bone marrow mesenchymal stem cells (BMSCs) differentiation dysfunction is a common pathological phenotype of several prevalent metabolic and genetic bone diseases. Pyruvate kinase muscle isoenzyme 2 (PKM2) regulates the last step of glycolysis, and its role in BMSCs differentiation is still unknown. In this study, the influence of PKM2 on osteogenesis and adipogenesis was assessed in vitro and in vivo. We found that DASA-58 (the activator of PKM2) reduced the enzymatic activity of ALP, and inhibited the levels of osteogenic marker genes, especially RUNX2, which is a crucial transcription factor for osteogenesis. Besides, we provided evidence that C3k, an inhibitor of PKM2, caused increase in mitochondrial membrane potential and maintained low levels of ROS, and promoted mitochondrial fusion. Furthermore, after treatment with DASA-58, the level of active β-catenin gradually decreased, which also inhibited the transport of active β-catenin into the nucleus, but C3k obviously promoted its nuclear translocation. As for adipogenesis, PKM2 activation increased the expression of adipogenic related genes and decreased active-β-catenin expression, whereas treatment of C3k had the opposite effect. In addition, C3k significantly attenuated ovariectomy-induced trabecular bone loss in vivo. Our findings helped uncover the molecular mechanisms underlying PKM2 regulation of BMSCs differentiation.
Highlights
Bone marrow mesenchymal stem cells (BMSCs) are self-renewable and multipotent stem cells with the capacity to differentiate into adipocytes, osteoblasts and chondrocytes [1]
As the activation of Wnt/β-catenin signaling is responsible for promoting osteogenesis and inhibiting adipogenesis, we testified by western blot that the expression of active-βcatenin reduced gradually when treated with DASA-58 from 0h to 48h, while Compound 3k (C3k) made the expression of activeβ-catenin increase gradually during this time (Figure 3D, 3E)
Osteogenesis and adipogenesis of BMSCs are not independent processes: molecular targets promoting one cell fate suppress the mechanisms stimulating the differentiation of the alternative lineage [5]
Summary
Bone marrow mesenchymal stem cells (BMSCs) are self-renewable and multipotent stem cells with the capacity to differentiate into adipocytes, osteoblasts and chondrocytes [1]. Several prevalent metabolic and genetic bone diseases, including diabetes, glucocorticoid (GC)-related osteonecrosis, osteoporosis and fibrous dysplasia, share a common pathological phenotype of BMSCs differentiation dysfunction [2,3,4]. Maintaining the balance of BMSCs differentiation is vital for bone homeostasis. Factors promoting osteogenesis are recognized as inhibitors for adipogenesis and vice versa [5]. These medical breakthroughs spurred an incredible interest in treating bone loss. Regulating the balance between osteogenesis and adipogenesis can provide appropriate therapeutic targets for preventing or treating insufficient bone formation and excessive bone marrow adipogenesis
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